Pulmonary macrophages may be the most important primary defense system protecting the lung from microbial invasions, inhaled pollutants, as well as from neoplastic growth. They may also play a significant role in the pathogenesis of chronic inflammation and autoimmune disease processes. Since germfree, colostrum-deprived, immunologically "virgin" piglets have absolutely no "resident" pulmonary macrophages (PAM) at birth and they could be maintained in a controlled environment, this gnotobiotic miniature swine model provides a unique opportunity for us to further investigate the following five specific aims: 1) ontogenic development and differentiation of "resident" pulmonary alveolar macrophages (PAM) in a controlled environment starting from the zero level; 2) Further characterization of PAM at different stages of differentiation by developing and utilizing monoclonal antibodies against differentiation antigens, Fc receptors, complement receptors, Ia antigens and other function-associated antigens of monocytes and PAM; 3) Role of PAM in the defense mechanisms against neoplasm as measured by tumoricidal effector functions of PAM at various stages of differentiation by spontaneous cellular cytotoxicity (SCC), antibody-dependent cellular cytotoxicity (ADCC), complement (C3)-dependent cellular cytotoxicity (C3DCC) and immobilized immune complex-dependent cellular cytotoxicity (IIC-DCC); 4) Role of PAM in the pathogenesis of tissue injuries and fibrotic lung diseases in vitro model; and 5) Activation and/or regulation of effector functions of PAM by microbial products, interferons, phorbol ester, prostaglandins and monoclonal antibodies against cell surface molecules. Investigations of ontogenic development, differentiation and tumorcidal effector functions of PAM, role of PAM in the pathogenesis of tissue injuries, and regulatory mechanisms of their effector functions may eventually lead to manipulation or control of the vital pulmonary defense system to confer on the host a better survival advantage.